The midbrain superior colliculus (SC) requires influence from visual cortex to play its critical role in subserving contralateral visual orientation: unilateral visual cortex lesions eliminate this capacity and induce contralateral hemineglect. Although insights from animal models of hemineglect suggest amelioration of the deficit is possible through a number of invasive interventions, none of these, unfortunately, offers viable therapeutic options for human patients. Our preliminary data indicate, however, that an appropriately structured rehabilitative strategy using cross-modal auditory-visual cues can permanently reinstate visuomotor capabilities in animals displaying a persistent and stable hemineglect following unilateral removal of all contiguous visual cortical areas. We suggest that a functionally reorganized cortico-SC circuit involving multisensory regions along the anterior ectosylvian sulcus (AES) emerges as a consequence of cross- modal training that now is capable of mediating visual orientation behaviors in the absence of visual cortex. Our objective will be to use physiological and behavioral techniques to evaluate the consequences of large visual cortex lesions on the physiological properties of neurons in the SC and AES in behaviorally-evaluated animals and to determine if, and how, these lesion-induced alterations are modified by cross-modal training. Our overarching hypothesis is that cross-modal training reinstates the 'lost' visual responsiveness in the SC, by providing it with another source of visual information - one derived from training-induced modifications of sensory responsiveness in AES, and conveyed to the SC via the AES-SC projection. We further suggest that the cross-modal plasticity in AES is, in part, dependent on mesocortical dopaminergic mechanisms. Understanding how the inherent plasticity of this circuit can be harnessed via non-surgical, behavioral techniques to ameliorate hemineglect will provide new insights that may facilitate strategies for dealing with this debilitating condition in human patients. PUBLIC HEALTH RELEVANCE: Understanding the lesion-induced neural changes produced in cortical - superior colliculus visual orientation network, and the potential plasticity of the remaining neural architecture, is a first step in the development of cross-modal rehabilitative strategies for ameliorating the deleterious consequences of visual hemineglect in human patients.